PPPARalpha was found to protect against acute chemical toxicity. Among the classic hepatotoxins is acetaminophen (APAP), which upon overdose, causes acute liver failure in humans and rodents PPARalpha controls the expression of genes encoding peroxisomal and mitochondrial fatty acid beta-oxidation enzymes. Activation of PPARalpha with the with the ligand Wy-14,643 or the fibrate drug fenofibrate, fully protects mice from APAP-induced hepatotoxicity. PPARalpha-humanized mice were also protected, whereas Ppara-null mice were not, thus indicating that the protection extends to human PPARalpha and is PPARalpha-dependent. This protection is due in part to induction of the PPARalpha target gene encoding mitochondrial uncoupling protein 2 (UCP2). Forced overexpression of UCP2 protected wild-type mice against APAP-induced hepatotoxicity in the absence of PPARalpha activation. Ucp2-null mice, however, were sensitive to APAP-induced hepatotoxicity despite activation of PPARalpha with Wy-14,643. Protection against hepatotoxicity by UCP2-induction through activation of PPARalpha is associated with decreased APAP-induced c-jun and c-fos expression, decreased phosphorylation of JNK and c-jun, lower mitochondrial hydrogen peroxide levels, increased mitochondrial glutathione in liver, and decreased levels of circulating fatty acyl-carnitines. These studies indicate that the PPARalpha target gene UCP2 protects against elevated reactive oxygen species generated during drug-induced hepatotoxicity and suggest that induction of UCP2 may also be a general mechanism for protection of mitochondria during fatty acid beta-oxidation. Previous studies revealed that PPARalpha can affect bile acid metabolism; however, the mechanism by which PPARalpha regulates bile acid homeostasis is not understood. In this study, a UPLC-ESI-QTOFMS-based metabolomics approach was used to profile metabolites in urine, serum, and bile of wild-type and PPARalpha-null mice following cholic acid (CA) dietary challenge. Metabolomic analysis showed that the levels of several serum bile acids, such as CA and taurocholic acid were significantly increased in CA-treated Ppara-null mice compared with CA-treated wild-type mice. Phospholipid homeostasis, as revealed by decreased serum lysophosphatidylcholine (LPC) 16:0 and LPC 18:0, and corticosterone metabolism noted by increased urinary excretion of 11beta-hydroxy-3,20-dioxopregn-4-en-21-oic acid and 11beta, 20alpha-dihydroxy-3-oxo-pregn-4-en-21-oic acid, were disrupted in CA-treated Ppara-null mice. The hepatic levels of mRNA encoding transporters Abcb11, Abcb4, Abca1, Abcg5, and Abcg8 were diminished in Ppara-null mice, leading to the accumulation of bile acids in the liver during the CA challenge. These observations revealed that PPARalpha is an essential regulator of bile acid biosynthesis, transport, and secretion.PXR is a major xenobiotic receptor that controls drug metabolism through its induction of drug transporters and enzymes that metabolize drugs such as CYP3A4. Recent studies have revealed that it is also a target for a new class of drugs used to treat intestinal inflammatory diseased such in irritable bowel syndrome and ]inflammatory bowel disease. Rifaximin, a non-systemic antibiotic that exhibits low gastrointestinal absorption, is a potent agonist of PXR that contributes to its therapeutic efficacy in inflammatory bowel disease. Rifaximin is a human PXR-specific ligand; it does not activate the mouse PXR. Thus. PXR-humanized mice expressing the human PXR on the mouse PXR null background were employed for these studies. To investigate the effects of long-term administration of rifaximin on the liver, PXR-humanized mice were administered rifaximin for six months; wild-type and Pxr-null mice were treated in parallel as controls. Histological analysis revealed time-dependent intense hepatocellular fatty degeneration and increased hepatic triglycerides in PXR-humanized mice, and not in wild-type and Pxr-null mice. After long-term treatment, PXR target genes were induced in small intestine and liver, with significant up-regulation in expression of hepatic genes related to triglyceride synthesis and lipid accumulation. However, no significant hepatic accumulation of rifaximin was found, even after six months of treatment, in PXR-humanized mice. Genes in small intestine that are involved in the uptake of fatty acids and triglycerides were induced along with increased triglyceride accumulation in intestinal epithelial cells of PXR-humanized mice; this was not observed in wild-type and Pxr-null mice. These findings suggest that long-term administration of rifaximin could lead to PXR-dependent hepatocellular fatty degeneration as a result of activation of genes involved in lipid uptake thus indicating a potential adverse effect of rifaximin on liver function after long-term exposure.Recent studies revealed that HNF4alpha is involved in the control of hepatocyte proliferation. HNF4alpha regulates genes involved in lipid and bile acid synthesis, gluconeogenesis, amino acid metabolism, and blood coagulation. In addition to its metabolic role, HNF4alpha is critical for hepatocyte differentiation, and loss of HNF4alpha is associated with hepatocellular carcinoma. The hepatocyte-specific Hnf4a knock-out mouse develops severe hepatomegaly and steatosis resulting in premature death, thereby limiting studies of the role of this transcription factor in the adult animal. In addition, gene compensation may complicate analysis of the phenotype of these mice. To overcome these issues, an acute Hnf4a knock-out mouse model was generated through use of the tamoxifen-inducible ErT2cre coupled to the serum albumin gene promoter. Microarray expression analysis revealed up-regulation of genes associated with proliferation and cell cycle control only in the acute liver-specific Hnf4alpha-null mouse. BrdU and ki67 staining confirmed extensive hepatocyte proliferation in this model. Proliferation was associated with induction of the hepatomitogen Bmp7 as well as reduced basal apoptotic activity. The p53/p63 apoptosis effector gene Perp was further identified as a direct HNF4alpha target gene. These data suggest that HNF4alpha maintains hepatocyte differentiation in the adult healthy liver, and its loss may directly contribute to hepatocellular carcinoma development, thus indicating this factor as a possible liver tumor suppressor gene.Type 2 diabetes is a risk factor for cancer. Obesity, insulin resistance, and type 2 diabetes form a tightly correlated cluster of metabolic disorders in which adipose is one of the first affected tissues. The role of hypoxia and HIF1 in the development of high-fat diet (HFD)-induced obesity and insulin resistance was investigated using animal models. On an HFD, adipocyte-specific ARNT knockout mice and adipocyte-specific HIF1alpha knockout mice exhibit similar metabolic phenotypes, including reduced fat formation, protection from HFD-induced obesity, and insulin resistance compared with similarly fed wild-type controls. The cumulative food intake remained similar; however, the metabolic efficiency was lower in adipocyte-specific HIF1alpha knockout mice. Moreover, indirect calorimetry revealed respiratory exchange ratios were reduced in adipocyte-specific HIF1alpha knockout mice. Hyperinsulinemic-euglycemic clamp studies demonstrated that targeted disruption of HIF1alpha in adipocytes enhanced whole-body insulin sensitivity. The improvement of insulin resistance is associated with decreased expression of Socs3 and induction of adiponectin. Inhibition of HIF1 in adipose tissue ameliorates obesity and insulin resistance. This study reveals that HIF1 could provide a novel potential therapeutic target for obesity and type 2 diabetes.